SCIENTIFIC AND COMMERCIAL DEVELOPMENT OF OLIGONUCLEOTIDES TO PROTECT NORMAL CELLS FROM TOXICITY SECONDARY TO CHEMOTHERAPY. THE OLIGONUCLEOTIDES WOULD BE USED TO TREAT SUCH CONDITIONS AS ALOPECIA (HAIR LOSS) AND MUCOSITIS.
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SCIENTIFIC AND COMMERCIAL DEVELOPMENT OF OLIGONUCLEOTIDES TO PROTECT NORMAL
CELLS FROM TOXICITY SECONDARY TO CHEMOTHERAPY. THE OLIGONUCLEOTIDES WOULD BE
USED TO TREAT SUCH CONDITIONS AS ALOPECIA (HAIR LOSS) AND MUCOSITIS.
National Cancer Institute Technology Transfer Branch CRADA Opportunity
Announcement Summary: The National Cancer Institute (NCI) is currently
seeking a Collaborator for a Cooperative Research and Development
Agreement (CRADA) to work with investigators in the Center for Cancer
Research (CCR) to develop novel oligonucleotides that can be used to
treat mucositis and alopecia (hair loss) during chemotherapy. These
oligonucleotides will be used clinically in the treatment of patients.
Development will include formulation of these oligonucleotides for
topical applications. The collaboration will involve all aspects of
therapeutic development from basic scientific inquiry to late stage
clinical trials that the selected sponsor will be required to partially
support. Background: While chemotherapeutic agents are often very
effective, there are often many side effects. Some side effects are
life-threatening, some result in significant morbidity, and others are
very significant from a psychosocial standpoint.Examples of these include
bone marrow suppression, mucositis and alopecia. While the use of
hematopoietic growth factors has substantially abrogated the concerns
over neutropenia, attempts to ameliorate mucositis and alopecia have been
less successful. Studies conducted at NCI have evaluated an approach to
prevent or abrogate chemotherapeutic side effects including alopecia and
mucositis. While the current data does not cover all chemotherapeutic
agents, with minor modifications this technology is expected to be
applicable to the majority, if not all, chemotherapeutic agents. The
basis for this approach is that regardless of target, most drugs bind to
a variety of macromolecules inside cells. For example, although DNA is
often regarded to be cisplatin's principal target, more that 90% of
administered cisplatin can be found in the cytosol bound to other
macromolecules. The observation that certain oligonucleotides can
interfere with drug activity is not unexpected. Many chemotherapeutic
agents such as adriamycin, cisplatin, and etoposide bind DNA and
therefore also bind oligonucleotides with variable affinities. Because
such oligonucleotides are active when present in the medium of cells
treated in vitro (they are charged and unable to penetrate cells) their
presence in the local environment of hair follicles, for example, could
prevent or abrogate drug induced cytotoxicity. It should be possible with
modifications and/or formulations to enhance penetration without
interfering with systemic activity of the chemotherapeutic. A relatively
unstable oligonucleotide could be used to achieve high local
concentrations but allow for its quick degradation if absorbed. Some
oligonucleotides may have broad specificity and therefore might be used
a broad-spectrum oligonucleotides when multi-agent chemotherapy is
administered. Success will require the administration of small molecules
locally during the period of drug exposure. This transient application
would be designed to achieve sufficient local concentration to bind toand
inactivate any drug that reached the target area. For example, local
application to the scalp in the form of a shampoo solution, or as a
liposomal formulation, or to the oral cavity in the form of an oral
solution could provide high local concentrations of the small molecule
antagonists. While "leaking" of such agents into the systemic circulation
could theoretically result in interference with a drug's activity against
a tumor, it is unlikely that the small amounts entering the circulation
would result in significant antagonism. Such a concern could be addressed
by appropriate in vivo models, or serum measurements in patients. While
the above discussion relates principally to drugs that bind DNA, this
concept is viewed as capable of being applied more broadly to include all
or nearly all chemotherapeutic agents which commonly cause sided effects.
A second potential approach for drugs that bind proteins, such as
paclitaxel, envisions the synthesis of small peptides to which such drugs
would bind with high affinities, achieving the same local effect as an
administered oligonucleotide. Preliminary data indicates that such
peptides can be identified and synthesized. Established screening
methodologies such as Phase Display could be used to identify these
peptides. Additional applications other than oncology can also be
envisioned, including, for example, male pattern hair loss. Systematic
experiments have been performed to date using a series of seven
oligonucleotides chosen in an initial screen of this concept. The results
have shown that with the right oligonucleotide of the right length,
protection of as mush as 100-fold can be achieved. These experiments have
provided insight into: (i) the optimal length; (ii) the optimal
concentration, and (iii) the mechanism of the protective effect by
demonstrating that protection is achieved by preventing drug from
entering the cells. These results are favorable with regard to the
possibility of development of this technology as a clinical strategy.
Proposed NCI Contribution: The NCI will synthesize the initial lot of two
to four oligonucleotides and conduct preclinical testing to determine the
efficacy of topically administered oligonucleotide(s) in preventing hair
loss following chemotherapy in an animal model. The NCI will initiate,
as appropriate, collaborative phase I clinical trials under its
intramural or extramural clinical trials network to determine the
efficacy of a topically administered oligonucleotide(s) in preventing
hair loss following chemotherapy in patients receiving chemotherapy.
Proposed CRADA Collaborator Contribution: The role of the CRADA
Collaborator will include, but not be limited to, formulation of the
initial lot of two to four oligonucleotides for topical administration
(encapsulation in liposomes is desirable), and manufacturing of the
topical formulation of at least one nucleotide in sufficient quantities
for use in clinical trials. Proposed Joint Contribution: The NCI and the
Collaborator will jointly design a CRADA Research Plan and will jointly
interpret the data generated under the Research Plan. The NCI and CRADA
Collaborator will collaborate in the planning and support of preclinical
and clinical development leading to FDA approval and marketing. Selection
Criteria for Choosing the CRADA Collaborator May Include: 1. A
demonstrated record of success in the commercial development and
production of products related to this area of technology, especially
experience in the topical formulation of drugs. 2. The willingness to
commit best effort and demonstrated resources to the research and
development of the oligonucleotides for clinical use. 3. The level of
financial and staffing support the CRADA Collaborator will provide for
CRADA-related activities. Willingness to cost share in preclinical and
clinical studies including the funding of personnel dedicated to
completion of the CRADA research project. 4. The willingness to cooperate
with the NCI in the timely publication of research results. 5. The
agreement to be bound by the appropriate Department of Health and Human
Services (DHHS) regulations relating to human subject research and to all
Public Health Service (PHS) policies relating to the use and care of
laboratory animals. 6. The willingness to accept the legal provisions and
language of the CRADA. These provisions govern the distribution of future
patent rights to CRADA inventions. Generally, the rights of ownership are
retained by the organization that is the employer of the inventor with
(1) the grant of a license for research and other Government purposes to
the Government when the CRADA Collaborator's employee is the sole
inventor, or (2) the grant of an option to elect an exclusive or
nonexclusive license to the CRADA Collaborator when the Government
employee is the sole inventor. Response Procedure: Interested parties
should notify the Technology Transfer Branch of the NCI in writing of
their interest in the CRADA collaboration no later than December 6, 2001.
The written notice should briefly address the selection criteria listed
above. Contact Information: CRADA Contact: Suzanne M. Frisbie, Ph.D. 6120
Executive Boulevard, Suite 450 Rockville, Maryland 20852 Phone:
301-496-0477; Fax: 301-402-2117 E-mail: Fris...@otd.nci.nih.gov WEB:
Click here to view the standard NIH CRADA document.,
http://ttb.nci.nih.gov/forms.html. E-MAIL: Click here to send a message
to the CRADA point of, Fris...@otd.nci.nih.gov. Posted 11/02/01
(W-SN5121O6).